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- Pathophysiology of Gout
- Symptoms and Signs of Gout
- Diagnosis of Gout
- Prognosis of Gout
- Treatment of Gout
- Key Points
- Asymptomatic Hyperuricemia
- Resources In This Article
- Drugs Mentioned In This Article
Gout is precipitation of monosodium urate crystals into tissue, usually in and around joints, most often causing recurrent acute or chronic arthritis. The initial attack of acute arthritis is usually monarticular and often involves the 1st metatarsophalangeal joint. Symptoms include acute pain, tenderness, warmth, redness, and swelling. Diagnosis requires identification of crystals in synovial fluid. Treatment of acute attacks is with anti-inflammatory drugs. The frequency of attacks can be reduced by regular use of NSAIDs, colchicine, or both and by treating hyperuricemia with allopurinol, febuxostat, or uricosuric drugs.
Gout is more common among men than women. Usually, gout develops during middle age in men and after menopause in women. Gout is rare in younger people but is often more severe in people who develop the disorder before age 30. Gout often runs in families.
The greater the degree and duration of hyperuricemia, the greater is the likelihood that gout will develop. Urate levels can be elevated because of
Why only some people with elevated serum uric acid (urate) levels develop gout is not known.
Decreased renal excretion is by far the most common cause of hyperuricemia. It may be hereditary and also occurs in patients receiving diuretics and in those with diseases that decrease GFR. Ethanol increases purine catabolism in the liver and increases the formation of lactic acid, which blocks urate secretion by the renal tubules. Lead poisoning and cyclosporine, usually in the higher doses given to transplant patients, damage renal tubules, leading to urate retention.
Increased production of urate may be caused by increased nucleoprotein turnover in hematologic conditions (eg, lymphoma, leukemia, hemolytic anemia) and in conditions with increased rates of cellular proliferation and cell death (eg, psoriasis, cytotoxic cancer therapy, radiation therapy). Increased urate production may also occur as a primary hereditary abnormality and in obesity, because urate production correlates with body surface area. In most cases, the cause of urate overproduction is unknown, but a few cases are attributable to enzyme abnormalities; deficiency of hypoxanthine-guanine phosphoribosyltransferase (complete deficiency is Lesch-Nyhan syndrome) is a possible cause, as is overactivity of phosphoribosylpyrophosphate synthetase.
Increased intake of purine-rich foods (eg, liver, kidney, anchovies, asparagus, consommé, herring, meat gravies and broths, mushrooms, mussels, sardines, sweetbreads) can contribute to hyperuricemia. However, a strict low-purine diet lowers serum urate by only about 1 mg/dL.
Urate precipitates as needle-shaped monosodium urate (MSU) crystals, which are deposited extracellularly in avascular tissues (eg, cartilage) or in relatively avascular tissues (eg, tendons, tendon sheaths, ligaments, walls of bursae) and skin around cooler distal joints and tissues (eg, ears). In severe, long-standing hyperuricemia, MSU crystals may be deposited in larger central joints and in the parenchyma of organs such as the kidney. At the acid pH of urine, urate precipitates readily as small platelike or irregular crystals that may aggregate to form gravel or stones, which may obstruct urine outflow. Tophi are MSU crystal aggregates that most often develop in joint and cutaneous tissue.
Acute gouty arthritis may be triggered by trauma, medical stress (eg, pneumonia or other infection), surgery, use of thiazide diuretics or drugs with hypouricemic effects (eg, allopurinol, probenecid, nitroglycerin), or indulgence in purine-rich food or alcohol. Attacks are often precipitated by a sudden increase or, more commonly, a sudden decrease in serum urate levels. Why acute attacks follow some of these precipitating conditions is unknown. Tophi in and around joints can limit motion and cause deformities, called chronic tophaceous gouty arthritis. Chronic gout increases the risk of developing secondary osteoarthritis.
Acute gouty arthritis usually begins with sudden onset of pain (often nocturnal). The metatarsophalangeal joint of a great toe is most often involved (called podagra), but the instep, ankle, knee, wrist, and elbow are also common sites. Rarely, the hip, shoulder, sacroiliac, sternoclavicular, or cervical spine joints are involved. The pain becomes progressively more severe, usually over a few hours, and is often excruciating. Swelling, warmth, redness, and exquisite tenderness may suggest infection. The overlying skin may become tense, warm, shiny, and red or purplish. Fever, tachycardia, chills, and malaise sometimes occur. Coexisting hypertension, hyperlipidemia, and obesity are common.
The first few attacks usually affect only a single joint and last only a few days. Later attacks may affect several joints simultaneously or sequentially and persist up to 3 wk if untreated. Subsequent attacks develop after progressively shorter symptom-free intervals. Eventually, several attacks may occur each year.
Tophi develop most often in patients with chronic gout, but they can rarely occur in patients who have never had acute gouty arthritis. They are usually firm yellow or white papules or nodules, single or multiple. They can develop in various locations, commonly the fingers, hands, feet, and around the olecranon or Achilles tendon. Tophi can also develop in the kidneys and other organs and under the skin on the ears. Patients with osteoarthritic Heberden nodes may develop tophi in the nodes. This development occurs most often in elderly women taking diuretics. Normally painless, tophi, especially in the olecranon bursae, can become acutely inflamed and painful. Tophi may even erupt through the skin, discharging chalky masses of urate crystals. Tophi may eventually cause deformities.
Chronic gouty arthritis can cause pain, deformity, and limited joint motion. Inflammation can be flaring in some joints while subsiding in others. About 20% of patients with gout develop urolithiasis with uric acid stones or Ca oxalate stones. Complications include obstruction and infection, with secondary tubulointerstitial disease. Untreated progressive renal dysfunction, most often related to coexisting hypertension or, less often, some other cause of nephropathy, further impairs excretion of urate, accelerating crystal deposition in tissues.
Cardiovascular disease and the metabolic syndrome are common among patients with gout.
Gout should be suspected in patients with acute mono- or oligoarticular arthritis, particularly older adults or those with other risk factors. Podagra and recurrent instep inflammation are particularly suggestive. Previous attacks that began explosively and resolved spontaneously are also characteristic. Similar symptoms can result from the following:
(however, CPPD generally occurs in larger joints, is not associated with tophi, and its clinical course is usually milder)
Acute rheumatic fever with joint involvement and juvenile idiopathic arthritis (however, these disorders occur mostly in young people, who rarely get gout)
RA (however, in RA, all affected joints flare, persist in flares for longer, and subside together, whereas in gout, inflammation is usually flaring in some joints while subsiding in others)
Acute fracture in patients unable to provide a history of injury
Acute calcific periarthritis caused by basic Ca phosphate crystal deposition disease and Ca oxalate crystal deposition disease
Palindromic rheumatism is characterized by acute, recurrent attacks of inflammation in or near one or occasionally several joints with spontaneous resolution; pain and erythema can be as severe as in gout. Attacks subside spontaneously and completely in 1 to 3 days. Such attacks may herald the onset of RA, and rheumatoid factor tests can help in differentiation; they are positive in about 50% of patients (these tests are positive in 10% of gouty patients also).
If acute gouty arthritis is suspected, arthrocentesis and synovial fluid analysis should be done at the initial presentation. A typical recurrence in a patient with known gout does not mandate arthrocentesis, but it should be done if there is any question of the diagnosis or if the patient’s risk factors or any clinical characteristics suggest infectious arthritis. Synovial fluid analysis can confirm the diagnosis by identifying needle-shaped, strongly negatively birefringent urate crystals that are free in the fluid or engulfed by phagocytes. Synovial fluid during attacks has inflammatory characteristics, usually 2,000 to 100,000 WBCs/μL, with > 80% polymorphonuclear WBCs. These findings overlap considerably with infectious arthritis, which must be excluded by Gram stain and culture.
Microscopic Examination of Crystals in Joints
An elevated serum urate level supports the diagnosis of gout but is neither specific nor sensitive; at least 30% of patients have a normal serum urate level during an acute attack. However, the serum urate level reflects the size of the extracellular miscible urate pool. The level should be measured on 2 or 3 occasions in patients with newly proven gout to establish a baseline; if elevated (> 7 mg/dL [> 0.41 mmol/L]), 24-h urinary urate excretion can also be measured. Normal 24-h excretion in people eating a regular diet is about 600 to 900 mg. Quantification of urinary uric acid can indicate whether hyperuricemia results from impaired excretion or increased production and is useful if a uricosuric drug is used for urate-lowering therapy. Patients with elevated urine excretion of urate are at increased risk of urolithiasis and uricosuric drugs are typically avoided.
Chronic gouty arthritis should be suspected in patients with persistent joint disease or subcutaneous or bony tophi. Plain x-rays of the 1st metatarsophalangeal joint or other affected joint may be useful. These x-rays may show punched-out lesions of subchondral bone with overhanging bony margins, most commonly in the 1st metatarsophalangeal joint; lesions must be ≥ 5 mm in diameter to be visible on x-ray. Joint space is typically preserved until very late in the course of disease.
Bone lesions are not specific or diagnostic but nearly always precede the appearance of subcutaneous tophi.
Diagnostic ultrasonography is increasingly used to detect a typical double-contour sign suggesting urate crystal deposition, but sensitivity is operator-dependent.
With early diagnosis, therapy enables most patients to live a normal life. For many patients with advanced disease, aggressive lowering of the serum urate level can resolve tophi and improve joint function. Gout is generally more severe in patients whose initial symptoms appear before age 30. The high prevalence of metabolic syndrome and cardiovascular disease probably increases mortality in patients with gout.
Some patients do not improve sufficiently with treatment. The usual reasons include nonadherence, alcoholism, and undertreatment by physicians.
Termination of an acute attack with NSAIDs or corticosteroids
Prevention of recurrent acute attacks with daily colchicine or an NSAID
Prevention of further deposition of MSU crystals, reduction in flare incidence, and resolution of existing tophi by lowering the serum urate level (by decreasing urate production with allopurinol, febuxostat, or uricase, or increasing urate excretion with probenecid or sulfinpyrazone)
Treatment of coexisting hypertension, hyperlipidemia, and obesity
NSAIDs are effective in treating acute attacks and are generally well tolerated. However, they can cause adverse effects, including GI upset or bleeding, hyperkalemia, increases in creatinine, and fluid retention. Elderly and dehydrated patients are at particular risk, especially if there is a history of renal disease. Virtually any NSAID used in anti-inflammatory (high) doses is effective and is likely to exert an analgesic effect in a few hours. Treatment should be continued for several days after the pain and signs of inflammation have resolved to prevent relapse.
Oral colchicine, a traditional therapy, often produces a dramatic response if begun soon after the onset of symptoms. A dose of 1.2 mg can be followed with 0.6 mg 1 h later; joint pain tends to decrease after 12 to 24 h and sometimes ceases within 3 to 7 days. If colchicine is tolerated, 0.6 to 1.2 mg once/day can be continued as the attack subsides. Drug interactions, especially with clarithromycin, may warrant reduction of dosage or use of other treatments.
IV colchicine is no longer available in the US because of major toxicity, usually related to inappropriate use or dosing.
Corticosteroids are sometimes used to treat acute attacks. Aspiration of affected joints, followed by instillation of corticosteroid ester crystal suspension, is very effective, particularly for monarticular symptoms; prednisolone tebutate 4 to 40 mg or prednisolone acetate 5 to 25 mg can be used, with dose depending on the size of the affected joint. Oral prednisone (about 0.5 mg/kg once/day), IM or IV corticosteroids, or single-dose ACTH 80 U IM is also very effective, particularly if multiple joints are involved. As with NSAID therapy, corticosteroids should be continued until after the attack fully resolves to prevent relapse.
In addition to NSAIDs or corticosteroids, supplementary analgesics, rest, ice application, and splinting of the inflamed joint may be helpful. Because lowering the serum urate level during an attack may prolong the attack or predispose to recurrence, drugs that lower the serum urate level should not be initiated until acute symptoms have been completely controlled. If corticosteroids, colchicine, and NSAIDs are contraindicated, an IL-1 antagonist, such as anakinra, can be used, although it is expensive.
The frequency of acute attacks is reduced by taking one to two 0.6-mg tablets of colchicine daily (depending on tolerance and severity). An extra two 0.6-mg tablets of colchicine taken at the first suggestion of an attack may abort flares. If the patient is taking prophylactic doses of colchicine and has had higher doses of colchicine to treat an acute attack within the past 2 wk, an NSAID should be used instead to try to abort the attack. A (reversible) neuropathy or myopathy can develop during chronic colchicine ingestion. This condition may occur in patients with renal insufficiency, in patients also receiving a statin or macrolide, or in patients with none of these risk factors. Attack frequency can also be decreased with daily low-dose NSAIDs.
Colchicine, NSAIDs, and corticosteroids do not retard the progressive joint damage caused by tophi. Such damage can be prevented and, if present, reversed with urate-lowering drugs. Tophaceous deposits are resorbed by lowering serum urate. Lowering serum urate may also decrease the frequency of acute arthritic attacks. This decrease is accomplished by
Hypouricemic therapy is indicated for patients with
Frequent or disabling attacks of gouty arthritis despite prophylactic colchicine, an NSAID, or both
Multiple comorbidities (eg, peptic ulcer disease, chronic kidney disease) that are relative contraindications to the drugs used to treat acute attacks (NSAIDs or corticosteroids)
Hyperuricemia is not usually treated in the absence of gout.
The goal of hypouricemic therapy is to lower the serum urate level. If tophi are not present, a reasonable target level is < 6 mg/dL (0.36 mmol/L), which is below the level of saturation (> 7.0 mg/dL [> 0.41 mmol/L] at normal core body temperature and pH). If tophi are present, the goal is to dissolve them, and this requires a lower target level. A reasonable target level is 5 mg/dL (0.30 mmol/L), and the lower the urate level, the faster tophi resolve. These target levels should be maintained indefinitely. Low levels are often difficult to maintain.
Drugs are effective in lowering serum urate; dietary restriction of purines is less effective, but high intake of high-purine food, alcohol (beer in particular), and nonalcoholic beer should be avoided. Carbohydrate restriction and weight loss can lower serum urate in patients with insulin resistance because high insulin levels suppress urate excretion. Intake of low-fat dairy products should be encouraged. Because acute attacks tend to develop during the first months of hypouricemic therapy, such therapy should be started in conjunction with once or twice daily colchicine or NSAIDs and during a symptom-free period. Resolution of tophi may take many months even with maintenance of serum urate at low levels. Serum urate should be measured periodically, usually monthly while determining required drug dosage and then yearly to confirm the effectiveness of therapy.
Allopurinol, which inhibits urate synthesis, is the most commonly prescribed hypouricemic therapy. Uric acid stones or gravel may dissolve during allopurinol treatment. Treatment begins with 100 mg po once/day and can be increased up to 800 mg po once/day, or even higher, to achieve target serum urate levels. Some clinicians recommend decreasing the starting dose in patients with renal insufficiency to decrease the incidence of rare but severe systemic hypersensitivity reactions; however, no data confirm the effectiveness of this intervention. The final dose of allopurinol should be determined by the target serum urate level. The most commonly used daily dose is 300 mg but this dose is adequate for < 50% of patients with gout. Adverse effects include mild GI distress and skin rash, which can be a harbinger of Stevens-Johnson syndrome, life-threatening hepatitis, vasculitis, or leukopenia. Adverse effects are more common among patients with renal dysfunction. Some ethnic groups (eg, Koreans with renal disease, Thai, and Han Chinese) are at high risk of allopurinol reactions; HLA B*5801 is a marker for that risk in these ethnic groups.
Febuxostat is a far more costly (in the U.S.) but potent inhibitor of urate synthesis. It is especially useful in patients who do not tolerate allopurinol, have contraindications to allopurinol, or in whom allopurinol does not sufficiently decrease urate levels. It is begun at 40 mg po once/day and increased to 80 mg po once/day if urate does not decrease to < 6 mg/dL. Febuxostat is contraindicated in patients taking azathioprine or mercaptopurine because it can decrease metabolism of these drugs. Transaminase levels can become elevated and should be measured periodically.
Uricase can also be given but is not yet routinely used. Uricase is an enzyme that converts urate to allantoin, which is more soluble. IV uricase transiently lowers serum urate by a large amount. It decreases urate so much that crystal deposits are partially solubilized, leading to intra-articular release and acute flares in up to 70% of uricase treatment courses. Allergic infusion reactions (anaphylaxis in 6.5% of patients and other infusion reactions in 25 to 40% of patients) may occur with uricase treatment despite pretreatment with corticosteroids and/or antihistamines. Pegloticase (a pegylated form of recombinant uricase) is usually used and is very expensive. Pegloticase is contraindicated in patients with G6PD deficiency because it can cause hemolysis and methemoglobinemia. Failure of urate levels to decrease to < 6 mg/dL after pegloticase treatment predicts pegloticase antibodies and a high risk of future allergic reactions. To prevent other urate-lowering drugs from masking the ineffectiveness of pegloticase, other urate-lowering drugs should not be used with pegloticase.
Uricosuric therapy is useful in patients who underexcrete uric acid, have normal renal function, and have not had renal stones. It usually involves probenecid or sulfinpyrazone. Probenecid treatment begins with 250 mg po bid, with doses increased as needed, to a maximum of 1 g po tid. Sulfinpyrazone treatment begins with 50 to 100 mg po bid, with doses increased as needed, to a maximum of 100 mg po qid. Sulfinpyrazone is more potent than probenecid but is more toxic. Low doses of salicylates may worsen hyperuricemia but only trivially.
Fluid intake ≥ 3 L/ day is desirable for all patients, especially those who chronically pass urate gravel or stones. Alkalinization of urine (with K citrate 20 to 40 mEq po bid or acetazolamide 500 mg po at bedtime) is also occasionally effective for patients with persistent uric acid urolithiasis despite hypouricemic therapy and adequate hydration. However, excessive urine alkalinization may cause deposition of Ca oxalate crystals. Extracorporeal shock wave lithotripsy may be needed to disintegrate renal stones. Large tophi in areas with healthy skin may be removed surgically; all others should slowly resolve under adequate hypouricemic therapy. Losartan has mild uricosuric effects.
Although increased purine intake and increased production can contribute to hyperuricemia, the most common cause of gout is decreased urate excretion secondary to diuretics, kidney disorders, or hereditary variations.
Suspect gout in patients with sudden, unexplained acute mono- or oligoarticular arthritis, particularly if the great toe is affected, or there is a prior history of sudden, unexplained acute arthritis with spontaneous remission.
Confirm the diagnosis by finding needle-shaped, strongly negatively birefringent urate crystals in joint fluid.
Treat acute attacks with oral colchicine, another NSAID, or a corticosteroid.
Decrease the risk of future attacks by prescribing colchicine, another NSAID, or, when indicated, drugs to decrease the serum urate level.
Give drugs that decrease serum urate if patients have tophi, frequent or severe attacks despite appropriate prophylaxis, urolithiasis, or multiple comorbidities that contraindicate the drugs used to relieve acute attacks.
Decrease urate levels usually by prescribing allopurinol or febuxostat.
Asymptomatic hyperuricemia is elevation of serum urate > 7 mg/dL (> 0.42 mmol/L) in the absence of clinical gout. Generally, treatment is not required. However, patients with overexcretion of urate who are at risk of urolithiasis may receive allopurinol. Accumulating data suggest that hyperuricemia may contribute to the progression of chronic kidney disease.
Drug NameSelect Trade
probenecidNo US brand name
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